9-128822530-C-T

Variant names:

• chr9-128822530-C-T
• rs769611074
• NM_004435.2:c.814C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004435.2(ENDOG):​c.814C>T​(p.Arg272Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000016 in 1,559,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ENDOG NM_004435.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

Genes affected

ENDOG (HGNC:3346): (endonuclease G) The protein encoded by this gene is a nuclear encoded endonuclease that is localized in the mitochondrion. The encoded protein is widely distributed among animals and cleaves DNA at GC tracts. This protein is capable of generating the RNA primers required by DNA polymerase gamma to initiate replication of mitochondrial DNA. [provided by RefSeq, Jul 2008]

SPOUT1 (HGNC:26933): (SPOUT domain containing methyltransferase 1) Enables miRNA binding activity. Involved in maintenance of centrosome location and production of miRNAs involved in gene silencing by miRNA. Located in kinetochore; mitotic spindle; and spindle pole centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000286112 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENDOG	NM_004435.2	c.814C>T	p.Arg272Trp	missense_variant	Exon 3 of 3	ENST00000372642.5	NP_004426.2
SPOUT1	NM_016390.4	c.*235G>A		3_prime_UTR_variant	Exon 12 of 12	ENST00000361256.10	NP_057474.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENDOG	ENST00000372642.5	c.814C>T	p.Arg272Trp	missense_variant	Exon 3 of 3	1	NM_004435.2	ENSP00000361725.4
SPOUT1	ENST00000361256	c.*235G>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_016390.4	ENSP00000354812.5
ENSG00000286112	ENST00000651925	c.*2405G>A		3_prime_UTR_variant	Exon 29 of 29			ENSP00000498386.1
SPOUT1	ENST00000467582	c.*195G>A		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000473640.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000427 AC: 7 AN: 163840 Hom.: 0 AF XY: 0.0000346 AC XY: 3 AN XY: 86664

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000398

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000806

Gnomad SAS exome AF: 0.0000856

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000468

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000163 AC: 23 AN: 1406824 Hom.: 0 Cov.: 31 AF XY: 0.0000158 AC XY: 11 AN XY: 694556

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000831

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000544

Gnomad4 SAS exome AF: 0.0000501

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.00000831

Gnomad4 OTH exome AF: 0.0000686

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000428 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.814C>T (p.R272W) alteration is located in exon 3 (coding exon 3) of the ENDOG gene. This alteration results from a C to T substitution at nucleotide position 814, causing the arginine (R) at amino acid position 272 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.81	P
Vest4		0.59
MutPred		0.83		Loss of phosphorylation at S269 (P = 0.0681);
MVP		0.90
MPC		0.43
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.79
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769611074; hg19: chr9-131584809;